Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity.

Magdi E A Zaki,Abdul Samad,Sami A Al-Hussain,Manoj K Sabnani,Vijay H Masand

doi:10.3390/ijms22158352

Abstract

Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful to identify crucial pharmacophoric features. The present work is based on a larger data set comprising 1121 diverse compounds to develop a QSAR model having a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The developed six parametric model fulfils the recommended values for internal and external validation along with Y-randomization parameters such as R2tr = 0.831, Q2LMO = 0.828, R2ex = 0.783. The present analysis reveals that anti-thrombotic activity is found to be correlated with concealed structural traits such as positively charged ring carbon atoms, specific combination of aromatic Nitrogen and sp2-hybridized carbon atoms, etc. Thus, the model captured reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with factor Xa. The analysis led to the identification of useful novel pharmacophoric features, which could be used for future optimization of lead compounds.

Highlights

World Thrombosis Day (WTD) is celebrated on 13 October each year in memory of Rudolf Virchow, who developed the concept of “thrombosis”
The present Quantitative Structure-Activity Relationship (QSAR) analysis was performed using a large dataset comprised of structurally diverse compounds with experimentally measured Ki in the range between 0.007 to nM
The present QSAR analysis was performed using a large dataset comprised of struc(GA-MLR) model to collect or extend thorough information about the pharmacophoric turally diverse compounds withbio-activity experimentally measured

Summary

Introduction

World Thrombosis Day (WTD) is celebrated on 13 October each year in memory of Rudolf Virchow, who developed the concept of “thrombosis”. Thrombosis, which is responsible for high mortality in the U.S and Europe, involves the formation of pathologically dangerous clots in the artery or vein [1]. The herpes simplex virus type-1 surface is responsible for the initiation of thrombus formation [7]. Thrombosis substantially decreases the survival rate [8,9]. The main reasons for thrombosis include age, surgery, trauma, inflammation, cancer, vessel injury, or overexpression of thrombogenic factors, to mention a few [1,8,9,10,11,12,13]. The understanding of thrombus development and its inhibition has gained a high interest to develop a safer and orally active anticoagulant for the treatment and prevention of thrombotic diseases

Methods

Results

Discussion

Conclusion